Pharmacologically active compounds

Abstract

The present invention relates to compounds of formula II wherein X, Y, R 2 , R 3 , R 4 and Ar are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

The invention claimed is: 
     
       1. A compound having the structural formula II shown below: 
       
         
           
           
               
               
           
         
         wherein: 
         X is CH or N; 
         Y is N or C—H; 
         R 2  is (1-6C)alkyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, a 5 or 6 membered heteroaryl, a 5 or 6 membered heteroaryl(1-2C)alkyl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, C(O)R 13 , C(O)OR 13 , OC(O)R 13 , C(O)N(R 14 )R 13 , S(O) x R 13  (where x is 0, 1 or 2), or SO 2 N(R 14 )R 13 ;
 and wherein R 2  is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O) x CH 3  (where x is 0, 1 or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl, 
 and wherein any (1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl, heterocyclyl, or (3-8C)cycloalkyl moiety present within a substituent group on R 2  is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , N(R d )OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c  (where y is 0, 1 or 2), SO 2 N(R d )R c , or N(R d )SO 2 R c , wherein R c  and R d  are each independently H or (1-4C)alkyl; 
 
         R 3  is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, halo, CF 3 , CN or (1-4C)alkoxy; 
         R 4  is hydrogen, fluoro, chloro or CF 3 ; 
         Ar has the formula: 
       
       
         
           
           
               
               
           
         
         wherein:
 (i) all of A 1 , A 2  and A 3  are CH; or 
 (ii) A 3  is CH and A 1  or A 2  are N or CH; 
 R 5  is cyano, (1-3C)alkyl, (1-3C)fluoroalkyl, (1-3C)alkoxy, (1-3C)fluoroalkoxy, halo, (1-3C)alkanoyl, C(O)NR 15 R 16  or S(O) 2 NR 15 R 16 , and wherein R 15  and R 16  are each independently H or (1-3C)alkyl, and wherein any alkyl or alkoxy moities present within a R 5  substituent group are optionally further substituted by hydroxy or methoxy; 
 R 6  is halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, ureido, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, 
 or R 6  is a group of the formula:
   -L 1 -L 2 -R 17    
 wherein
 L 1  is absent or a linker group of the formula —[CR 18 R 19 ] n — in which n is an integer selected from 1, 2, 3 and 4, and R 18  and R 19  are each independently hydrogen or (1-2C)alkyl; 
 L 2  is absent or is O, S, SO, SO 2 , N(R 20 ), C(O), C(O)O, OC(O), CH(OR 20 ), C(O)N(R 20 ), N(R 20 )C(O), N(R 20 )C(O)N(R 21 ), S(O) 2 N(R 20 ), or N(R 21 )SO 2 , wherein R 20  and R 21  are each independently selected from hydrogen or (1-2C)alkyl; and 
 R 17  is (1-6C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-4C)alkyl, heteroaryl, heteroaryl-(1-4C)alkyl, heterocyclyl, or heterocyclyl-(1-4C)alkyl, 
  and wherein R 17  is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, NR 22 R 23 , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl, (1-5C)alkylsulphonyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, CONR 22 R 23 , and SO 2 NR 22 R 23 ; wherein R 22  and R 23  are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R 22  and R 23  can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring ring; 
  and wherein when said substituent group comprises an alkyl, cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is optionally further substituted by hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3 , (1-2C)alkyl, (1-2C)alkoxy, SO 2 (1-2C)alkyl or NR e R f  (where R e  and R f  are each independently hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl); 
 
 or R 17  is a group having the formula:
   -L 3 -L 4 -R 24    
 
 wherein
 L 3  is absent or a linker group of the formula —[CR 25 R 26 ] n — in which n is an integer selected from 1, 2, 3 or 4, and R 25  and R 26  are each independently hydrogen or (1-2C)alkyl; 
 L 4  is absent or is O, S, SO, SO 2 , N(R 27 ), C(O), C(O)O, OC(O), CH(OR 27 ), C(O)N(R 27 ), N(R 27 )C(O), N(R 27 )C(O)N(R 28 ), S(O) 2 N(R 27 ), or N(R 28 )SO 2 , wherein R 27  and R 28  are each independently hydrogen or (1-2C)alkyl; and 
 R 24  is (1-6C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-4C)alkyl, heteroaryl, heteroaryl-(1-4C)alkyl, heterocyclyl, or heterocyclyl-(1-4C)alkyl; 
 
 
 
         R 13  is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl, and wherein R 13  is optionally further substituted by one or more substituents selected from hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3  (1-2C)alkyl and (1-2C)alkoxy; 
         R 14  is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl-(1-2C)alkyl, and wherein R 14  is optionally further substituted by one or more substituents selected from hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3 , (1-2C)alkyl and (1-2C)alkoxy; 
         subject to the proviso that:
 X can only be N when Y is N; 
 when X and Y are both N, R 3  is H or fluoro; 
 
         or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
       2. A compound according to  claim 1 , wherein said compound has one of the structures IIa, IIb or IIc shown below: 
       
         
           
           
               
               
           
         
         and wherein Ar, R 2 , R 3  and R 4  are as defined in  claim 1 . 
       
     
     
       3. A compound according to  claim 1 , wherein R 2  is (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, a 5 or 6 membered heteroaryl, a 5 or 6 membered heteroaryl(1-2C)alkyl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, C(O)R 13 , C(O)OR 13 , OC(O)R 13 , C(O)N(R 14 )R 13 , S(O) x R 13  (where x is 0, 1 or 2), or SO 2 N(R 14 )R 13 ;
 and wherein R 2  is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O) x CH 3  (where x is 0, 1 or 2), methylamino, dimethylamino, phenyl, phenyl(1-2C)alkyl, a 5 or 6 membered heteroaryl, a 5 or 6 membered heteroaryl(1-2C)alkyl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl, 
 and wherein any (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl, heterocyclyl, or (3-8C)cycloalkyl moiety present within a substituent group on R 2  is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , N(R d )OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c  (where y is 0, 1 or 2), SO 2 N(R d )R c , or N(R d )SO 2 R c , wherein R c  and R d  are each independently H or (1-4C)alkyl. 
 
     
     
       4. A compound according to  claim 1 , wherein R 2  is (1-6C)alkyl, a 5 or 6 membered heteroaryl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, C(O)N(R 14 )R 13 , S(O) x R 13  (where x is 0, 1 or 2), or SO 2 N(R 14 )R 13 ;
 and wherein R 2  is optionally substituted by one or more substituent groups fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O) x CH 3  (where x is 0, 1 or 2), methylamino or dimethylamino, 5 or 6 membered heteroaryl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl, or (3-8C)cycloalkyl(1-2C)alkyl, 
 and wherein any (1-4C)alkyl, (1-4C)alkoxy, heteroaryl, heterocyclyl, or (3-8C)cycloalkyl moiety present within a substituent group on R 2  is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , N(R d )OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c  (where y is 0, 1 or 2), SO 2 N(R d )R c , or N(R d )SO 2 R c , wherein R c  and R d  are each independently H or (1-4C)alkyl. 
 
     
     
       5. A compound according to  claim 1 , wherein R 3  is hydrogen, (1-2C)alkyl or (3-6C)cycloalkyl. 
     
     
       6. A compound according to  claim 1 , wherein R 3  is hydrogen. 
     
     
       7. A compound according to  claim 1 , wherein R 4  is hydrogen, (1-2C)alkyl, fluoro, chloro or CF 3 . 
     
     
       8. A compound according to  claim 1 , wherein R 4  is hydrogen. 
     
     
       9. A compound according to  claim 1 , wherein R 5  is (1-3C)alkyl, (1-3C)alkoxy, (1-3C)fluoroalkoxy or halo, and wherein any alkyl or alkoxy moities present within a R 5  substituent group are optionally further substituted by methoxy. 
     
     
       10. A compound according to  claim 1 , wherein R 5  is OCH 3  or Cl. 
     
     
       11. A compound according to  claim 1 , wherein R 6  is halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl,
 or a group of the formula:
   -L 1 -L 2 -R 17    
 
 wherein 
 L 1  is absent or a linker group of the formula —[CR 18 R 19 ] n — in which n is an integer selected from 1 and 2, and R 18  and R 19  are each independently hydrogen or methyl; 
 L 2  is absent or is O, S, SO, SO 2 , N(R 20 ), C(O), C(O)O, OC(O), CH(OR 20 ), C(O)N(R 20 ), N(R 20 )C(O), N(R 20 )C(O)N(R 21 ), S(O) 2 N(R 20 ), or N(R 20 )SO 2 , wherein R 20  and R 21  are each independently hydrogen or (1-2C)alkyl; and 
 R 17  is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, heteroaryl, or heterocyclyl, 
 and wherein R 17  is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, NR 22 R 23 , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl, (1-5C)alkylsulphonyl, 3 to 6 membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl-(1-2C)alkyl, CONR 22 R 23 , and SO 2 NR 22 R 23 ; wherein R 22  and R 23  are each independently hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R 22  and R 23  can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring; 
 and wherein when said substituent group comprises an alkyl, cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is optionally further substituted by hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3 , (1-2C)alkyl, (1-2C)alkoxy, SO 2 (1-2C)alkyl or NR e R f  (where R e  and R f  are each independently hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl); 
 or R 17  is a group having the formula:
   -L 3 -L 4 -R 24    
 wherein 
 L 3  is absent or a linker group of the formula —[CR 25 R 26 ] n — in which n is an integer selected from 1 and 2, and R 25  and R 26  are each hydrogen; 
 L 4  is absent or is O, S, SO, SO 2 , N(R 27 ), C(O), C(O)O, OC(O), C(O)N(R 27 ), N(R 27 )C(O), S(O) 2 N(R 27 ) or N(R 28 )SO 2 , wherein R 27  and R 28  are each independently hydrogen or (1-2C)alkyl; and 
 R 24  is (1-6C)alkyl, phenyl, phenyl-(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-4C)alkyl, 5 or 6-membered heteroaryl, 5 or 6-membered heteroaryl-(1-2C)alkyl, 4 to 6-membered heterocyclyl, or 4 to 6-membered heterocyclyl-(1-2C)alkyl. 
 
 
     
     
       12. A compound according to  claim 1 , wherein R 6  is halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl,
 or a group of the formula:
   -L 1 -L 2 -R 17    
 
 wherein 
 L 1  is absent or a linker group of the formula —[CR 18 R 19 ] n — in which n is an integer selected from 1 and 2, and R 18  and R 19  are each independently hydrogen or methyl; 
 L 2  is absent or is O, S, SO, SO 2 , N(R 20 ), C(O), C(O)O, OC(O), CH(OR 20 ), C(O)N(R 20 ), N(R 20 )C(O), N(R 20 )C(O)N(R 21 ), S(O) 2 N(R 20 ), or N(R 20 )SO 2 , wherein R 20  and R 21  are each independently hydrogen or (1-2C)alkyl; and 
 R 17  is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, heteroaryl, or heterocyclyl, 
 and wherein R 17  is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, NR 22 R 23 , (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl, (1-5C)alkylsulphonyl, 3 to 6 membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl-(1-2C)alkyl, CONR 22 R 23 , and SO 2 NR 22 R 23 ; wherein R 22  and R 23  are each independently hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R 22  and R 23  can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring; 
 and wherein when said substituent group comprises an alkyl, cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is optionally further substituted by hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3 , (1-2C)alkyl, (1-2C)alkoxy, SO 2 (1-2C)alkyl or NR e R f  (where R e  and R f  are each independently hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl). 
 
     
     
       13. A compound according to  claim 1 , wherein R 8 , R 9 , and R 13  are each independently hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, 3 to 6 membered heterocyclyl, or 3 to 6 membered heterocyclyl-(1-2C)alkyl, and wherein R 8 , R 9 , and R 13  are optionally further substituted by one or more substituents selected from hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3 , methyl and methoxy. 
     
     
       14. A compound according to  claim 1 , wherein R 7 , R 10 , and R 14  are independently hydrogen or (1-4C)alkyl. 
     
     
       15. A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.